DE2606140A1 - NEW DERIVATIVES OF 2-PHENYL-2-HYDROXYAETHYLAMINE - Google Patents

Description

New derivatives of 2-phenyl-2-hydroxyethyl

amines

The invention relates to new Z-phenyl - ^ - hydroxyethylamine derivatives of the formula

CH-CH-NH-Ch ₉ -CH-CH ₉ -O —ί ι ί> / τ \

Ii 2 ι 2 W ^ yiy (ι),

OH R ₄ OH

and their salts, the preparation of these compounds and their use in pharmaceuticals and as intermediates for the preparation of pharmaceuticals; the bases of the formula I can be present as racemates, as mixtures of racemates or in the form of individual optical antipodes or can be contained in the salts.

709834/1037

The radicals R to Rg in formula I have the following Bede.υ do ff:

R ₁ : V? 5.seι αtoffatom, Hal ^ genatom, hydroxy, amino, alkyl, alkoxy or acylamido group;

Rp: hydrogen atom, hydroxy, alkyl, alkoxy or Carbo cam! Jog group;

R,: hydrogen or halogen atoms, alkyl or alkoxy groups ;

R ^: hydrogen, methyl or ethyl group;

R ₅ and Rg! Hydrogen atom, halogen atom, alkyl, alkoxy, benzyloxy, hydroxy, amino, cyano, carboxy, carbalkoxy, carboxamido, alkylenecarboxamido or acylamido group,
with the proviso that,

if Rj ^ hydrogen, 4-hydroxy or 4-chlorine, R ₂ hydrogen, R, hydrogen, R ^ methyl and

R = hydrogen or 2-halogen, Rg does not represent 4-hydroxy or 4-benzyloxy. As far as alkyl or alkoxy groups are mentioned in the above definitions or other groups which are alkyl · - or Containing alkoxy groups, those alkyl or alkoxy groups are meant which have 1 to 4 carbon atoms and can be straight-chain or branched. The acyl radicals in the acylamido groups are derived from lower aliphatic carboxylic acids or lower alkanesulfonic acids, the alkylene carboxamido groups contain lower alkylene groups.

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BATH ORIGINAL

The following meanings of substituents should be emphasized:

R,: hydrogen, chlorine or bromine atoms, hydroxy group, C -, - C _n -alkyl / especially methyl, Cj-Cp-alkoxy, above all methoxy, acetylamido, propionylamido or methanesulfonamides;

Rp: hydrogen atom, hydroxy group e, C-j-Cp-alkyl, before especially methyl, or C-j-Cp-alkyl, especially methyl, or C - ^ - C2 "-alkoxy, especially methoxy;

R ,: hydrogen, chlorine or bromine atom, hydroxyl group, C - Cp-alkyl, especially methyl, or C -, - Cp-alkoxy,

especially methoxy;
R ^ ₊ : hydrogen atom or methyl group;

R ₅ : hydrogen, fluorine, chlorine or bromine atom, C - ^ - C ₂ -alkyl, especially methyl, C - ^ - C ₂ -alkoxy, especially methoxy, a hydroxy, cyano, carboxy, Carboxamido, benzyloxy or amino group, a carbalkoxy, alkylenecarboxamido or acylamido group, each containing up to 3 carbon atoms.

The new compounds may look like the following per se known processes:

1. Cleavage of the protective group or the protective groups from a compound of the formula

R ₈ ' ^R 10

><^> CH0H-CHR, ₁ -NR, ₇ -CH _o -CH0H-CH _o -0

in which R, and R ^ have the meaning given above and

709834/1037

Rr ₇ for hydrogen or an arylmethyl radical,

Rg for R, or one by hydrogenolytic or hydrolytically cleavable protective group, substituted hydroxyl or amino group,

R ₀ for R ₀ or a hydroxyl group substituted by a protective group which can be split off hydrogenolytically or hydrolytically,

R ₁₀ and R ₁₁ for R ^ respectively. R ^ or a hydroxy or amino group substituted by a protective group which can be split off hydrogenolytically or hydrolytically

v / obei at least one of the radicals R ₇ to R -, ^ represents or contains a protective group.

Particularly suitable protective groups are arylmethyl, alkanoyl and aroyl groups, tetrahydropyranyl and, for adjacent OH groups, bifunctional groups, such as a diaryl methylene group. Examples of the various types of protective groups are the benzyl radical and substituted benzyl radicals, lower aliphatic acyl radicals, benzoyl radicals and the diphenylmethylene radical.

Arylmethyl groups on nitrogen are catalytic Hydrogenation in the presence of conventional hydrogenation catalysts, e.g. platinum, palladium, Raney nickel removed, arylmethyl groups or diarylraethylene groups on oxygen v / grounding by catalytic hydrogenation or by hydrolysis with acids; Alkanoyl, aroyl or tetrahydropyranyl radicals are split off by hydrolysis.

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2606H0

- ar-

If the starting material has substituents which should also be included in the end product, but which are below the conditions of the splitting off of the protective groups could be changed, is familiar to the person skilled in the art Way to pay attention to the choice of sufficiently mild reaction conditions. However, it is also possible for example, to start from starting materials in which Rp. or Rg represent carbalkoxy or carboxamido groups, and these groups simultaneously into the corresponding ones during the hydrolytic deprotection Convert end products with a free carboxy group. This also applies analogously to the other methods of Invention.

The starting materials of the formula II can according to customary Methods can be obtained, for example by reacting an amine of the formula

0-CH ₂ -CHOH-CH ₂ -NHR ₇ (III)

with a compound of the formula ^R 8 ^ O _v

CH - CHR ₄ or ^N > £ ^ N _r _ CHOH-CHR ₄ -X

(IVa) (IVb)

(X: halogen atom, e.g. the chlorine atom) in a manner known per se.

709834/1037

Also analogous to procedure 2 described below the compounds of formula II can be obtained. Depending on the reducing agents, the erythro- or the threo form can be obtained.

2. Reduction of the carbonyl group in a compound of

Formula ^R l -

■ Y-CHR ₄ -NH-CH ₂ -Y »-CH ₂ -O

wherein one of the radicals Y and Y 'represents the group -CO-, the other stands for -CHOH-.

The carbonyl group is reduced

a) with complex hydrides, e.g. lithium aluminum hydride, sodium or potassium borohydride, sodium bis (2-methoxyethoxy) -aluminium hydride (SDMA.), or

b) with hydrogen in the presence of a hydrogenation catalyst, e.g. platinum, palladium or Raney nickel.

Assuming a compound of the formula V in which Y is the carbonyl and R ^ is an alkyl group, so the end products can be obtained in both threo and erythro form. With those mentioned under a) Reducing agents are obtained compounds of the formula I in the threo form, while the application of the under b) said agent leads to the erythro-shape.

709834/103?

The starting materials can be obtained by conventional methods, e.g. by adding a compound of the formula

- Y-CHR ^ -X

(VI)

with a compound of the formula

0-CH ₂ -Y • -CH ₂ -NH ₂

implements.

/ _VII ^

3. Implementation of a compound of the formula ^R l

with a compound of the formula

Rr

(VIII)

(ix)

Instead of the compound VIII one can also use the chlorohydrin of the formula

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2606U0

tr

R.

-CHCH-CHR ₄ -Cl

Cx)

-ζ,

go out, from which compound VIII is formed under the reaction conditions.

4. Reduction of marine bases of the formulas

respectively.

CHOH-CHR ₄ -N = CH-CHOH-Ch ₂ -O

(XIa)

R.

R ₂ R.

CHOH-CR ₄ = N-CH ₂ -CHOH-Ch ₂ -O

(XI

with hydrogen and conventional hydrogenation catalysts or with complex hydrides.

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5. Reduction of acid amides of the formulas

R-.

respectively.

(XIIa)

-R _c

^R 6

CHOH-CHR ₄ -NH-Co-CHOH-CH ₂ -O

(XIIb)

with complex hydrides, e.g. lithium aluminum hydride, SDMA or diborane.

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6. Hydrolysis of oxazolidinones or oxazolidines of the formula

respectively.

- CHOH-CHR ₄ -N -CH ₂

R CE

( ^{R: co} »CHR ¹ , where R« C ₁ -C ₃ -AlCyI or aryl)

CHR ₄

N-CH ₀ -CHOH-CH ₀ -O 2 2

(XIIIb)

The hydrolysis takes place in an alkaline, possibly also an acidic medium.

It is expedient to work at an elevated temperature in a mixture of water and a water-miscible mixture Solvent, e.g., methanol, ethanol, dioxane, in the presence of a base, preferably an alkali base.

The process is particularly suitable for the production of such end products which do not contain any phenolic OH groups contain. It can also be used to produce those starting materials for process 1 that are resistant to hydrolysis Contain protecting groups.

70S83A / 1037

-Mr-

Oxazolidinones of the formulas XIIIa and XIIIb can be obtained, for example, according to the reaction scheme below:

R.

CHOh-CHR ₄ -NH-CO-OC ₂ H ₅

(XIV)

+ CH ₂ - -CH-CH ₂ -O

(XV)

CH

O = C

(XIIIa)

R-,

CH "^ ~~ ^ CHRy

(XVI)

+ C ₂ H ₅ O-CO-NH-Ch ₂ -CHOH-CH ₂ O

(XVII)

CH

ι Γ

YEAR

4th

N-CH ₂ -CHOH-CH ₂ -

(XIIIb)

70983A / 1

A *

7. Implementation of azetidinols of the formula

γ. CHOH-CHR ^ -N CH ₂

CH ₂ -CHOH

with phenols of the formula

(XVIII)

(XIX).

The reaction takes place at elevated temperature, expediently in a higher-boiling anhydrous solvent or solvent mixture, e.g. in benzyl alcohol, in Presence of an alkali hydroxide, preferably under a nitrogen atmosphere. The procedure is generally used to obtain compounds of the formula I which do not contain any phenolic hydroxyl groups.

One possibility for the production of the starting materials is given in the following reaction scheme:

- CHOH-CHR ₄ -NH ₂ + Cl-CHg-CH-—

(XX)

(XXI)

CHOH-CHR ₄ -N-

-CH,

CH ₂ - CHOH

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For the processes according to the invention, optically active precursors can also be used and, if appropriate, pure optical isomers can be obtained directly. Racemates obtained in the process can be separated into the optically active compounds by customary methods .

If antipodal separation is envisaged, then in process 2 , for example , one starts from compounds of the formula V in the R or S form, ie from a uniform configuration in the CHOH group. When the carbon group is reduced , the RS and RR forms or the SS or the are created, depending on the starting material

SR form.

The bases of the formula I are optionally converted into salts by customary methods or, if they are present as salts, into salts of other acids or into free bases.

All starting materials can be obtained by methods known per se.

The compounds of formula I have cardiovascular effects and are also vasodilator, antihypertensive and antiarrhythmic. They can be used, for example, as active ingredients of selectively effective cardiac agents, since they combine a positive inotropic effect with only a small frequency-increasing effect.

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This is shown in bPispie "¹;, wise err. Results of the test on the isolated seaweed auricle. The usual test with 1 / .g active ingredient / ml obtained
Values for change in amplitude (A) and change in frequency (F) are for

l _ [? _ (A-hyaroxyphenyl) -2-hydroxyäthylamino] -3- (A-cyaiiophenoxy) -rroTianol- (2) A: + 37 %, F: + 7 %
and for

! - [·? - (3r ^ • -7) ihydroxyphenyl) -2-hydrox3'-ethylamino] -3- (4-tolyloxy) -propanol-2 · A: + 36 %, F: - 3%.

I ^{1-1 For} use, the active ingredients according to the invention are processed with the auxiliaries customary in galenic pharmacy to form customary pharmaceutical forms,

zl ·. z \ i tablets, coated tablets, capsules, tinctures, injection solutions, suppositories.

The single dose is between about 1 and 100 mg,
preferably 5-50 mg, depending on
Application form, active ingredient and body weight of the person to be treated.

Examples of formulations are given below.

Tablets composition:

Active ingredient according to the invention 5 parts by weight

Stearic acid 6 parts by weight

Dextrose 589 parts by weight

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BATH ORIGINAL

Components are never processed in the usual way into tablets weighing 600 mg / icht, if desired the active ingredient content can be increased or decreased and the
Grape consumption decreased accordingly or
increase.

Suppositions

composition

Active ingredient according to the invention 50 parts by weight

Lactose, powdered 45 parts by weight

Kakp.o butter 1605 parts by weight

<~> he components become I in the usual way ^; upp ^ s'torien v-_n 1.7 g weight, processed.

Capsules

composition

Active ingredient according to the invention 10 parts by weight

Lactose 490 parts by weight

Corn starch 400 parts by weight

Each 1000 mg of the finely powdered mixture will be
filled in hargelatine capsules.

The following examples are intended to illustrate the manufacturing processes explain the active ingredients in more detail:

7 0 9 I ■ :. U '\ 3 7

BATH ORIGINAL

dd

Example 1

1- [2- (4-Hydroxyphenyl) -2-hydroxy-ethyl-amino] -3- (4-tc> lyloxy) -prepanol-2-hydrochloride

12 g of a-aminomethyl-4-benzyloxy-benzyl alcohol and 9g of 2- (4-tolyloxymethyl) oxirane are dissolved in 60 ml of alcohol dissolved and refluxed for 5 hours. One lets Cool over wake, vacuum and dry. The compound obtained, 1- (2- (4-benzyloxyphenyl) -2-hydroxyethylamino] -3- (4-tolyloxyl) -propanol-2, is dissolved in 50 ml of methanol and after addition of palladium / carbon 10 Jöig catalytically at room temperature and normal pressure debenzylated. After the calculated amount of hydrogen has been taken up, the catalyst is suctioned off and the solvent distilled off on a Rotavapor. The residue is dissolved in acetonitrile and made more ethereal with the calculated amount Hydrochloric acid added .. The hydrochloride which crystallizes out des l- [2- (4-hydroxyphenyl) -2-hydroxy-ethylamino] -3- (4-tolyloxy) -propanol-2-is vacuumed and dried. The substance melts at 146 ° C.

Example 2

1- [2- (4-Hydroxyphenyl) -2-hydroxy-ethylamino1-5- (3-tolyloxy) ■

propanol-2-hydrochloride

a) 15 g of 4'-benzyloxy-2-bromo-acetophenone are in 150 ml Acetonitrile dissolved. While stirring, 13.5 g of l-benzylamino-3- (3-tolyloxy) -propanol-2 (melting point = 76-77 °) and 6.9 g of anhydrous potassium carbonate are added. It is refluxed for 3 hours, cooled and filtered off with suction. The calculated amount of ethereal hydrochloric acid is added to the organic phase. One leaves overnight the hydrochloride of 4'-berizyloxy-N-benzyl-N- [2-hydroxy-3- (3-tolyLoxy) ~ propyl J-2-amino-ncetophenone (m.p. 147 ° C) crystallize out, sucks off and dries.

0 3 4/1337

b) 21 g of the above HCl salt are dissolved in water until the reaction is weakly alkaline, ammonia is added and the mixture is extracted with ether. After evaporation of the ether in vacuo, the residue is dissolved in 200 ml of alcohol and by adding 1.5 g of sodium borohydride to give 1- [2- (4 ~ benzyloxyphenyl) -2-hydroxy-N-benzyl-ethylamino] -3- (3 -tolyloxy) -propanol-2 reduced. For working up, the mixture is first made slightly acidic with dilute acetic acid, the alcohol is distilled off in vacuo, the residue is dissolved in water and, after the addition of ammonia, extracted with ether. The solvent is distilled off in vacuo, the residue is taken up in acetonitrile and acidified with ethereal hydrochloric acid. The precipitated hydrochloride is filtered off with suction and dried; (M.p. 128 ° C).

c) To remove both benzyl groups, 10 times the amount of the hydrochloride obtained under b) is dissolved Methanol. After adding palladium / carbon, the calculated amount of hydrogen is added to Hydrogenated normal conditions. The catalyst is filtered off with suction and evaporated to dryness in a vacuum. The residue is dissolved hot in acetonitrile. The crystalline 1- [2- (4-hydroxyphenyl) -2-hydroxyätiiyl is obtained on cooling amino] -3- (3-tolyloxy) -propanol-2-hydrochloride

from melting point 149 - 150 ⁰ C.

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BATH ORIGINAL

l>) 21 g of the above HCl aize are dissolved in water bi <: to the scm / «cn alkaline reaction, with ammonia added and 'extracted with ether. After evaporation of the ether in vacuo, the residue is dissolved in ΓΟΟ ml of alcohol and by adding 1.5 g Νε triuaibo *. hydride to 1- [2- (4-benzyloxyphenyl) -2-hydro;: y-N-beriZyl ~ ethylamino] -3 - (3-tolyloxy) -propanol-2 reduced. For work-up, it is first used with diluted Acetic acid made weakly acidic, the alcohol is distilled off in vacuo, the residue in V / ater dissolved and extracted with ether after the addition of ammonia. The solvent is distilled off in vacuo, the residue taken up in acetonitrile and acidified with ethereal hydrochloric acid. That precipitated hydrochloride is filtered off with suction and dried; (M.p. 128 ° C).

c) To remove both benzyl groups, the hydrochloride obtained under b) is dissolved in 10 times the amount of methanol. After adding palladium / carbon, hydrogenation is carried out under normal conditions until the calculated amount of hydrogen is absorbed. It is suctioned off from the catalyst and concentrated in vacuo to dryness _o The residue is dissolved in hot acetonitrile. The crystalline 1- [2- (4-hydroxyphenyl) -2-hydroxyethyl am: 'no] -3- (3-tolyloxy) propane 1-P-hydrochloride with a temperature of 149 ° -15 ° C. is obtained on cooling.

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Example 3

1- [2- (3-hydroxyphenyl) -2-hydroxy-ethylamino1-3- (4-

tolyloxyl) -propanol-2-hydrochlor.id

15.4 g of 3'-benzyloxy-cc-bromomethyl-benzyl alcohol become together with 13 »5 g of N-benzyl-2-hydroxy-3- (4-tolyloxy) propylamine and 6.9 g of anhydrous potassium carbonate in 100 ml of acetonitrile refluxed for 5 hours. It is filtered off with suction and ethereal hydrochloric acid is added until the reaction is weakly acidic. The unusual one The hydrochloride is immediately dissolved in methanol without further purification and after the addition of palladium / carbon catalytically debenzylated. The catalyst is filtered off with suction, evaporated to dryness in vacuo, and the residue is dissolved in Acetonitrile and let cool slowly. The next day the hydrochloride of 1- [2- (3-hydroxyphenyl) -2-hydroxy-ethylamino] -3- (4-tolyloxy) -propanol-2 vacuumed and dried; Mp * 138-140 ° C.

Example 4

1-[ 2- (3-Hydroxyphenyl) -2-hydroxy-ethylamino1 -3- (2-cyano-

phenoxy) propanol-2-fumarate

a) 11.3 g of 2- (3-benzyloxyphenyl) ethylene oxide (bp _{Q 1} 152 155 ° C) and 16.8 g of l-benzylamino-3- (2-cyanophenoxy) -propanol-2- (mp. 181- 182 ° C) in 50 ml of alcohol are refluxed for 8 hours. The alcohol is then distilled off in vacuo, the residue is taken up in ethyl acetate and ethereal hydrochloric acid is added until the reaction is weakly acidic. It is left to stand overnight, suction filtered and dried. The hydrochloride of 1- [2- (3-beiizyloxyphenyl) -2-hydroxy-N-ben: 2-ethylamino] -3- (2-cyanophenoxy) -propanol-2 melts at 151-152 ° C.

7 0 9 ΰ 3 A / 1 0 3 7

b) For debenzylation, the substance obtained in a) is dissolved in methanol and, after addition of palladium / carbon, is shaken at room temperature until the calculated amount of oxygen has been absorbed. The catalyst is then filtered off with suction, the residue is dissolved in hot alcohol and the calculated amount of fumaric acid is added. It is allowed to cool slowly, suction filtered and dried. The fumarate of 1- [ '·' - " (^ -hydroxyphenyl) -2-hydroxy-ethylamino] -3- [2-cyanophenoxy] -propanol-2 melts at 165-167 ° C.

example 3

1- I2- ( 3,5-D! Hydroxyphenyl) -2-hydroxy-ethylamino] -3- (4-

tolyloxy) propanol-2-hydrochloride

5 * 4 g of p-cresol are dissolved in 50 ml of acetonitrile. 13.8 g of anhydrous potassium carbonate and 23.4 g of 3,5-dibenzyloxy-cc-N- (3-chloro-2-hydroxypropyl) aminomethylbenzyl alcohol hydrochloride are added. The mixture is refluxed for 5 hours, filtered off with suction and then evaporated to dryness. The residue is dissolved in methanol and catalytically debenzylated under normal conditions. It is filtered and distilled off, the residue is dissolved in hot acetonitrile, the calculated amount of ethereal hydrochloric acid is added and the mixture is allowed to cool slowly. The crystals of 1- [2- (3,5-dihydroxyphenyl) -2-hydroxyethylamino] -3- [4-tolyloxy] -propanol-2-hydrochloride are filtered off with suction and dried ] . Mp. 169-170 C.

Example 6

1- [2- (4-hydroxyphenyl) -2-hydroxy-ethylamino j-3- [2-

methoxyphenoxy] propanol-2-sulfate

19 ° g l-amino-2- (2-methoxy-phenoxy) -propanol-2, together with 28.6 g of 4-benzyloxy-phenylglyoxal-hemiacetal (mp. 77 - 80 ⁰ C) in 500 ml of methanol by heating to

709334/1037

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4o ° C dissolved. It is left to stand at room temperature overnight. The next day is cooled to ⁰ C and 7.4 -1O s sodium borohydride in portions. The temperature should ·! here and not rise at five hours post-reacting about 0 ⁰ C. It is left to stand overnight in the refrigerator and the precipitated crystals of 1- [2- (4-benzyloxyphenyl) -2-hydroxy-ethylamino] -3- [2-methoxyphenoxy] -propanol-2 are filtered off with suction. Dissolve in 20 times the amount of methanol, add palladium / carbon and remove the benzyl protective group by catalytic hydrogenation. After the catalyst has been filtered off with suction, the solvent is distilled off in vacuo, the backwater is dissolved in a little warm alcohol and the calculated amount of concentrated sulfuric acid is added. The liquid of 1- [2- (4-hydroxyphenyl) -2-hydroxy-ethylamine-I-3- [2-methoxyphenoxy] -propanol-2 slowly crystallizes out, is filtered off with suction and then dried; Fp, 187 188 ⁰ C.

Example 7

j. - [2- (4-Hydrophenyl) -2-hydroxy-ethylamino] -5- [4-carboxami-

cof.henoxvi-propanol-2-hydrochloride

a) 14.9 "g of l-benzylamino-3- (4-carboxamido-phenyl) -

Propanone-2 and 11.3 g of 4- (benzyloxyphenyl) -äthylenoryd in 100 ml of alcohol are refluxed for 8 hours. The reaction is allowed to continue overnight at room temperature and 2 g of sodium borohydride are then added. First, it is stirred for 2 hours at room temperature and then at 70 ⁰ C. P hours distilled the alcohol off in vacuo, the residue is treated with water vm>'acidified with acetic acid. Then several times with ethyl acetate. The solvent is removed in vacuo, the residue in isopropanol in the

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BATH ORIGINAL

- rr-

Boiling heat dissolved and slowly cooled. The precipitating crystals of 1- [2- (4-benzyloxylphenyl) -2-hydroxy-N-benzyl-ethylamino] -3- [4-carboxamidophenoxy] -propanol-2 are filtered off with suction after some time and dried; Mp. 111-112 ⁰ C.

b) The dibenzyl compound obtained under a) is dissolved in 10 times the amount of methanol and, after the addition of palladium / carbon, is catalytically debenzylated. After the calculated amount of hydrogen has been taken up, the catalyst is suctioned off, the solvent is distilled off in vacuo, the residue is dissolved in alcohol and the calculated amount of ethereal hydrochloric acid is added. The hydrochloride of 1- [2- (4-hydroxyphenyl) -2-hydroxy-ethylamino] -3- (4-carbamidophenoxy) -propanol-2 crystallizes out. It is suctioned off and dried in a circulating air drying cabinet; Mp. 179-180 ⁰ C.

Example 8

1- [2- (4-Hydroxy-phenyl) -2-hydroxy-ether-lamino] -3-phenoxy-propanol-2-fumarate

10.2 g of 4-benzyloxy-N - [(2-hydroxy-3-phenoxy) propyl] -N-benzyl-mandelic acid amide are dissolved in 200 ml of absolute tetrahydrofuran. While stirring and at the same time Introducing nitrogen, 10 g of lithium aluminum hydride are added. It is refluxed for 5 hours, cools down and decomposes the excess lithium aluminum hydride by slowly adding water. One decants and narrow to dryness. The residue is taken up in methanol and after addition of palladium / charcoal catalytically debenzylated. After the calculated amount of hydrogen has been taken up, the catalyst is suctioned off and concentrated in a vacuum, absorbs a little alcohol and adds a hot alcoholic solution with the calculated amount

709334/1037

Fumaric acid too. The fumarate of l- [2- (A-hydroxyphenyl) -2-hydroxy-ethylamino] -3-phenoxypropanol-? (Pp. 186 ⁰ C).

example

1- [, 2- (3 ₁ 4-dichloro] dhenyl) -2 - hydroxy - etherealaniino ^ ~ 3-phenoxypropanol-2 ~ formate

A solution of 6 g of 3- [2- (3,4-dichlorophenyl) -2-hydroxyethylamino] -5-phenoxymethyloxazolidinone in 50 ml of ethanol, to which 10 g of potassium hydroxide and 20 ml of water are added, is refluxed for 90 minutes. After cooling, the alcohol is distilled off in vacuo. The aqueous phase is extracted twice with ether, the ethereal phase is washed with water and dried over magnesium sulfate. After subscription ^{1 of} ether, the residue is dissolved in a little ethanol, - formic acid and slowly ether are added. The formate crystallizes out colorless. pp.

Example 10

1- (2-Phenyl-2-hydroxy-ethylamino) -3- (2-cyanophenoxy) -propanol-2-hydrochloride

2 g of l- (2 ~ phenyl-2-hydroxyethyl) -azetidinol-3 are in 15 ml Dissolved benzyl alcohol and added 1.25 g of 2-cyanophenol and 0.1 g of potassium hydroxide. Then is stirred for 5 hours heated to about 140 ° C. After cooling, ether is added and extracted three times with 15 ml each time to give hydrochloric acid. the aqueous phase is washed with ether and made alkaline with sodium hydroxide. The basic parts are taken up in ether and washed with water. The organic phase is then dried over magnesium sulfate the ether is distilled off. The remaining basic residue is dissolved in ethyl acetate and up to weakly acidic reaction mixed with ethereal hydrochloric acid. The hydrochloride is obtained as colorless crystals.

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(D j nac! PK 3 3 "1 α ι · » 0 3. I j

The compounds listed in the table also correspond to the above examples manufactured:

OO CaJ

Table of compounds of the formula R ₂

CHOH-CHr ^ -NH-CH ₂ -CHOH-CH ₂ -O

No. ^R l R ₂ ^R 3 ^R 4 ^R 5 ^R 6 Salt * / m.p. [ ⁰ C] 1 H H H CHj (erythro) 2-CN H Cl / 169-170 2 H H H CH ₅ (threo) 2-CN H FU / 177-179 3 4-OH 3-OH 2-CH ₃ H 4-CH ₃ H Cl / 244 (decomp.) 4th 4-OH H H H 3-CN H Cl / 154-156 VJI 4-OH H H H 2-CH ₃ H FU / 123-125 6th 4-OH H H H 2-CN H Cl / 135-136 7th 4-OH H H H 4-CN H Cl / 157-159 8th 3-OH H H H 2-CH ₃ H FU / 122 9 3-OH 5-OH ■ H H 4-CN H FU / 152-155 10 4-OH • H H H 4-OCH ₃ H Cl / 142-143 11 4-OH H H H 3-OCH ₃ 4-OCH ₃ Cl / 177-179 12th 3-Cl 4-Cl H H H H FO / 189-190 13th 4-OH 3-NH ₂ H H 2-CH ₃ H Cl / 210 (decomp.)

Continuation table

14 15 16 17

Salt / m.p. [ ⁰ C]

4-OH 4-OH 4-OH 4-OH

3-NH-COCH,

3-OCH ₃ 3-CONH ₂

* Ci; Hydroc

ilorid

NS:

H H H H

Fumarate

H
H
H
H

FO: formate

2-CH

4-CH ₂ -CONH ₂
4-CH ₃
4-CH,

H
H

3-CH
H

Cl / 158-159

FU / 171-172

Cl / 148-149

ei / 195-196

ro cr>

Claims (4)

Patent claims i-Phenyl-2-h / firoxyethylamine derivatives of the formula CH-CH-NH ^ CH ₂ -Ch-CH ₂ -O OH k _h . OH in the R _{1 is} hydrogen, halogen, hydroxy, amino, alkyl, alkoxy or acylamido, R _{2 is} hydrogen, hydroxy, alkyl, alkoxy or carboxamido, R, hydrogen or halogen, alkyl or alkoxy, R. is hydrogen, methyl or ethyl and R ₅ and Rg are hydrogen, halogen, alkyl, alkoxy, benzyloxy, hydroxy, amino, cyano, carboxy, carbalkoxy, carboxamido, alkylenecarboxamido or acylamido means j with the proviso that, if R, hydrogen, 4-hydroxy or 4-chlorine, R ₂ hydrogen) R, hydrogen, R, methyl and R _{5 is} hydrogen or 2-halogen; Rg does not represent 4-hydroxy- or 4-benzyloxy, in the form of racemates, racemates mixed and single optical antipodes, as well as the respective salts. 2. Medicinal preparations, characterized by a Content of one or more compounds according to Claim 1. 709834/1037 ORIGINAL INSPECTED 2606HQ 3. Vei'fahren for the production of connections according to Claim 1, characterized in that a) from a compound of the formula '8th X ^ -Y-CHOH-CHR ₄ -NR ₇ -CH ₂ -CHOH-Ck ₂ -O (II) in which R, and R ^ have the meaning given above and R _{7 stands} for hydrogen or an arylmethyl radical, for R ₁ or a hydroxyl or amino group substituted by a hydrogenolytically or hydrolytically removable protective group, for R ₂ or one that can be removed by a hydrogenolytically or hydrolytically Protective group substituted hydroxyl group, and for respectively. or one through one Hydrogenolytically or hydrolytically removable protective group are substituted hydroxyl or amino group where at least one of the radicals R ₇ to R ₁₁ represents or contains a protective group, the protective group or protective groups are split off hydrogenolytically or hydrolytically, or that one b) in a compound of the formula (V) 709834/1037 wherein one of the radicals Y and Y ^{1 stands} for the group -CO-, the other for -CHOH-, the carboxyl group is reduced or that one c) a compound of the formula R-. CHR with a compound of the formula 0-CH ₂ -CHOH-CH ₂ -NH ₂ implement or that one cO a Schiff base of the formula (VIII) (IX) CHOH-CHR ₄ -N = Ch-CHOH-CH ₂ -O (XIa) R ₂ n- CH0H-CR ₄ "N-CH ₂ -CH0H-CH ₂ -0 709834/103 7 ^R 6 (XIb) - S8- - with hydrogen and conventional hydrogenation catalysts or with complex hydrides or that one e) acid amido of the formula R. or R-. (XIIa) CHOH-CHR ₄ -Nh-CO-CHOH-CH ₂ -O (XIIb) reduced with complex hydrides ₉ or that f) an oxazolidinone or oxasolidine of the formula CHOH-CHR ^ -N CH ₂ R CH-CH ₀ -O . (XIIIa) 709834/1037 _CH CHR, i ,> , -JQ ^ ^ n-ch _? - :: hoch-ch ₂ -o. (XLiIb; hydrolyzed or that one
g) an acetidinol of the formula R-, '^ CHOH-CHR ₄ -N-CH ₂ CH ₂ -CHOH with phenols of the formula (XVIII) (XIX) reacts in the presence of an alkali hydroxide and since.; the resulting R-dc-rnates, if appropriate by customary methods, in di-, · optically active compounds au Γ i.rennc and / or da. Bases of the formula I which are initially incident, if appropriate, are converted into salts by customary methods : - i converts the compounds obtained as salts dei 'ΐ ^Γ ' ΐ "ο" 1 into salts of acidic acids or into free bases 709834/1037 BATH ORIGINAL 2606Ί40 - 59-- 4. Process for the preparation of medicaments, characterized in that active ingredients according to Claim 1 with the auxiliaries customary in galenical pharmacy processed into common drug forms. Verwedue ee m.— 709834/1037